Method for treating a periodontal disease

ABSTRACT

A method for treating a periodontal disease affecting a periodontal pocket of a patient. The method comprises inserting an oral delivery device into the periodontal pocket at a frequency of about once every 4 days to about once every 6 weeks. The oral delivery device is a controlled release solid unit dosage form suitable for insertion into a periodontal pocket of a patient, comprising a therapeutically effective amount of at least one anti-inflammatory agent, at least one antibacterial agent, or the combination of at least one anti-inflammatory agent and at least one antibacterial agent.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 14/507,493 filedOct. 6, 2014, which is a continuation of U.S. Ser. No. 13/277,784 filedOct. 20, 2011, now U.S. Pat. No. 8,865,198 issued on Oct. 21, 2014,which claims the benefit of U.S. Ser. No. 61/406,288 filed on Oct. 25,2010, the disclosures of which are incorporated by reference in theirentirety.

FIELD OF THE INVENTION

This invention relates to an improved method for treating a periodontaldisease.

BACKGROUND OF THE INVENTION

Local delivery systems (LDS) of antibacterial agents have shownbeneficial effect on pocket reduction and inflammation in chronicperiodontitis patients. An example of such a system is the Periochip®.PerioChip® (chlorhexidine gluconate) is a small, rectangular chip forinsertion into periodontal pockets. Each PerioChip contains 2.5 mg ofchlorhexidine gluconate in a biodegradable matrix of hydrolyzed gelatin(cross-linked with glutaraldehyde). PerioChip also contains glycerin andpurified water. Treatment is recommended to be administered once everythree months in pockets with a remaining pocket depth of ≧5 mm.

Absorbable periodontal implants have been described which used ahydroxypropylcellulose polymer. Suzuki, Y., et. al., (U.S. Pat. No.4,569,837) discloses the use of water-soluble polymeric substances (suchas methyl cellulose, gelatin, etc.) as a polymeric matrix for aperiodontal implant. Lading, P. (U.S. Pat. No. 5,143,934) describes theincorporation of metronidazole into a gel that semi-solidifies in theperiodontal pocket as a liquid crystalline formulation. The antibioticdrug is released over about one day as the gel dissolves in the gingivalcrevicular fluid.

A biodegradable sustained-release composition has been described byFreidman, M. et al., (U.S. Pat. No. 5,023,769) which is capable ofdelivering a pharmacological composition for a period of time sufficientto treat a periodontal infection. The pharmacological agent(chlorhexidine antiseptic) comprises a polymeric matrix containing aplasticizing agent, and the active agent, wherein the polymeric matrixcomprises a cross-linked, water-insoluble protein formed from a watersoluble protein.

The compositions described above have varying efficacy in reducing thebacterial load of the periodontal pocket and in reducing pocket depthand gingival level of attachment. None of the above mentionedformulations are particularly efficacious in causing alveolar boneregrowth or even in arresting alveolar bone resorption.

One of the drugs that is known in its ability to reduce alveolar boneresorption is flurbiprofen (FBP). FBP is a non-steroidalanti-inflammatory drug (NSATD) which also exhibits analgesic andanti-pyretic activity. FBP inhibits prostaglandin synthesis byinhibition of cyclooxygenase, an enzyme that catalyses the formation ofprostaglandin precursors from arachidonic acid. Wechter, W. J. (Europeanpatent No. 137,668 B1) suggests the use of FBP for the treatment of boneresorption and the inducing of bone growth.

Williams et al (J. Perio. Res. 19:633-637, 1984; 22:403-407, 1987;23:166-169, 1988) and Jeffcoat et al (J. Perio. Res. 21:624-633, 1986)demonstrated that devices and topical application of FBP to beagle dogsfor 6-12 months inhibited alveolar bone loss in naturally occurringperiodontitis. Offenbacher et al (J. Perio. Res. 22:473-481,1987)demonstrated that FBP administered deviceatically to Macaca mulattamonkeys with experimentally induced periodontal disease resulted insignificant inhibition of attachment, bleeding on probing and gingivalredness. Chung et al (J. Perio. Res. 32:172-175,1997) tested drug (FBPand others)-loaded biodegradable membrane for guided bone regeneration(GBR). The loaded membrane was effective for osteoid tissue and new boneformation in the bony defect prepared in rat calvaria to compare withthat by unloaded membrane. The successful results seen in animal modelstreated with FBF led to the conclusion that clinical studies could beperformed in patients with moderate to severe periodontal disease.

Jeffcoat et al (J. Perio. Res. 23:381-385, 1988) were the firstinvestigators who demonstrated the clinical effects of FBP on theprogression of periodontal disease. As evidenced by standardizedradiography and reduced radiopharmaceutical uptake, treatment with FBP(100 mg/day) for two months increased bone metabolism. A study for 24months using FBP by Williams et al (J. Dental Res. 70:468,1991) foundthat the FBP-oral administration treated patient group showed reductionin bone loss. This demonstrated that FBP treatment can be a significantinhibitor of alveolar bone loss. Heasman et al (J. Clin. Periodontol,20:457-464, 1993) examined the effect of FBP given topically(toothpaste, 1% w/w) twice daily for 12 months to patients withperiodontal disease. The FBP treated group showed statisticallysignificant bone gain. This suggests that the topical application of FBPmay have a positive bone gain effect in humans.

Dimani, N. C. (U.S. Pat. No. 5,447,725) suggests a delivery device thathardens on contact with the periodontal tissue after a solvent isleached out and that releases FBP or other drugs in the periodontalpocket. The material is inserted into the periodontal pocket as a gelfrom a syringe and hardens in situ. Syringing an exact dose of a gelinto a body crevice such as a periodontal pocket and having a known doseof the drug solidifying therein is difficult to carry out and difficultto control.

Friedman et al (U.S. Pat. No. 5,023,082) discloses biodegradablesustained-release liquid compositions capable of achieving the sustainedrelease of a pharmaceutical agent such as an anti-inflammatory agent.The liquid precursor compositions can be formed into solid implantdevices after administration which may be used to treat diseases such asperiodontal disease which require prolonged drug release.

Friedman et al (U.S. Pat. No. 5,160,737) discloses a liquid methacrylicacid copolymer composition that contains a release adjusting agent and apharmacological agent. The composition forms a solid film upon drying,and is capable of accomplishing the sustained release of thepharmacological agent such as to permit its use in the treatment orprevention of dental or dermatological conditions.

Lerner et al (U.S. Pat. No. 6,197,331) discloses a controlled-releasesolid composition for the oral cavity or “pharmaceutical oral patch”that adheres to hard dental surfaces, such as teeth and dentures, andreleases an active pharmaceutical agent into the oral cavity. Release ofthe agent is for a predetermined period of time and at a predeterminedsustained concentration. The site of action of the agent is local ordevice.

Ulrich et al (U.S. Pat. No. 6,685,928) discloses methods of promotinghealing through enhanced regeneration of tissue (e.g. hard tissue orsoft tissue) by contacting the tissue or the surrounding tissue with ananti-inflammatory agent in a carrier comprising aromatic polyanhydrides.These methods are useful in a variety of dental and orthopedicapplications.

WO 2004/084873 discloses an oral delivery system for the treatment ofperiodontal disease, being in a solid unit dosage form foradministration to a patient and comprising: (i) a biodegradable orbioerodible pharmaceutically acceptable polymer; (ii) a therapeuticallyeffective amount of at least one antibacterial agent; and (iii) atherapeutically effective amount of at least one anti-inflammatoryagent, the relative weight ratio between the antibacterial agent and theanti-inflammatory agent ranking from about 7:1 to about 1:5. The systemmay further comprise at least one of a cross-linking agent, aplasticizing agent, a \vetting agent, a suspending agent, a surfactantand a dispersing agent.

SUMMARY OF THE INVENTION

It has now been surprisingly discovered that the oral delivery device asdisclosed in the prior art may be administered at a significantly higherfrequency than was previously known, with improved therapeutic results.

Thus, the present invention provides a method for treating a periodontaldisease affecting a periodontal pocket of a patient in need comprisinginserting an oral delivery device into the periodontal pocket at afrequency of about once every 4 days to about once every 6 weeks,

wherein the oral delivery device is a controlled release solid unitdosage form suitable for insertion into a periodontal pocket of apatient, comprising a therapeutically effective amount of an activeingredient selected from:

-   -   i) at least one anti-inflammatory agent,    -   ii) at least one antibacterial agent, and    -   iii) the combination of at least one anti-inflammatory agent and        at least one antibacterial agent.

In one embodiment, the oral delivery device further comprises abiodegradable pharmaceutically acceptable water-insoluble polymer in theform of a matrix, wherein the active ingredient is dispersed ordissolved within the matrix.

In another embodiment, the biodegradable pharmaceutically acceptablewater-insoluble polymer is degradable by enzymatic degradation, physicaldisintegration or a combination thereof.

In one embodiment, the water-insoluble polymer comprises a water-solublepolymer rendered water-insoluble by the addition of a cross-linkingagent in an amount sufficient to render said polymer water-insoluble,while permitting the release of said anti-inflammatory agent or saidantibacterial agent from said delivery device.

In a further embodiment, the oral delivery device optionally comprises aplasticizing agent.

In another embodiment, the oral delivery device optionally comprises atleast one of a surfactant, a wetting agent, a suspending agent and adispersing agent.

In a further embodiment, the oral delivery device optionally comprisesan enzymatically biodegradable pharmaceutically acceptable water solublepolymer dispersed or dissolved within the matrix.

In one embodiment, the oral delivery device is inserted at a frequencyof once every 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45 or 46 days.

In a further embodiment, the oral delivery device is inserted at afrequency of every 7-14 days.

In a still further embodiment, the oral delivery device is inserted at afrequency of once every two weeks for a period of the earlier of threemonths or until healing, with healing being defined as a PeriodontalPocket Depth (PPD) of less than 5 mm.

In another embodiment, the frequency of insertion is decreased as thePPD decreases.

In this specification, the following terms have the following meanings:

“solid unit dosage form” means not a liquid, and includes semi-solid,paste, ointment and gel.

“controlled release” means not an immediate release of all of the activeingredient, and includes sustained release, delayed release and extendedrelease.

In another aspect of the invention, there is provided a use of an oraldelivery device as defined in the specification in the preparation of adevice adapted for insertion into the periodontal pocket for thetreatment of periodontal disease according to the method of theinvention.

In one embodiment of the invention, the physical disintegration is byhydration and swelling of the water-insoluble polymer. In anotherembodiment, the biodegradable water-insoluble polymer is not degradableby hydrolysis. In a further embodiment, the water-insoluble polymer ispresent at a concentration of from about 20% to about 70%.

One embodiment of the delivery device that would be most advantageouswould be one that has an exact dose of drug predetermined, is easy toinsert, is retained in a periodontal pocket without the need ofadhesives to keep it from falling out, gives sustained release of theanti-inflammatory drug over several days, and biodegrades so that thereis no need for the removal of the device after the treatment period.Ease of insertion and dose control can be obtained by having thedelivery device preformed into a rigid thin film that easily slips intoa crevice such as a periodontal pocket with the aid of a simpletweezers. The adherence of the dosage form to the inside of the pocketis obtained by the drug delivery device softening and swelling, therebyadhering to the inside of the pocket.

The precursor solutions to drug delivery devices of this invention areused to form drug delivery devices that are polymeric solids that may becast as films, pellets, granules, cylinders or any other convenientshape for the task at hand. The devices allow local delivery of the drugat the target site. The devices may be used as implants for the extendeddelivery of drug. The devices may also be used as inserts to bodycrevices as well as drug delivery devices in the body in general and, inone embodiment, in the oral cavity. Most preferentially, the devices maybe used as an insert into periodontal crevices or pockets, or as animplant in periodontal surgery.

A drug delivery device for implantation in the body or insertion in acrevice in the body will preferentially be one that can target the drugto the organ desired, deliver the drug in a local fashion, and degradein the body to harmless by-products so that the device need not beremoved when it has finished its useful function. Preformed deviceswould negate the dose control problem. Both the in situ and preformedpolymers of this sort tend to biodegrade slowly and are useful fordelivery devices designed for prolonged release of the active ingredientin a 1-2 weeks time frame. They do, however, biodegrade to amino acidswhich are biocompatible and non toxic. Poly amino acids and proteinshave been found useful as the basis for drug delivery devices sincetheir degradation products are harmless amino acids and theirbiodegradation is facile in many parts of the body.

Useful polymers for drug delivery include cross-linked water-solubleprotein, cellulose or cellulose derivative, starch or starch derivative,glyceryl monostearate, carbomer, PVP (polyvinylpyrrolidone), gum, acaciagum, guar gum, polyvinyl alcohol, polyhydroxyethyl metacrylate,polyhydroxymethyl metacrylate polyacrylic acid, polyacryl amide andpolyethylene glycols, an enzyme and fibrinogen. For example, proteinsderived from connective tissue such as collagen and gelatin, andproteins of the albumin class that may be derived from milk, serum, orfrom vegetable sources may be used, with gelatin and hydrolyzed gelatinbeing the most preferable. In one embodiment, the hydrolyzed gelatin mayhave a molecular weight in the range of 1-20 K Dalton. Proteins,however, tend to be water soluble. In a soluble form the protein is lessuseful for sustained release of a drug since its solubilization willremove it from the body in too short a time. It is therefore desirableto render the protein water insoluble while maintaining its ability tobiodegrade through normal enzymatic processes and permitting the releaseof the anti-inflammatory agent from the delivery device. Thisinsolubilization of the protein may be done by making insoluble salts ofthe protein, insoluble complexes of the protein or most preferably bycrosslinking the protein. In one embodiment, a water-soluble polymer iscross-linked by a curing process in the presence of a cross-linkingagent, wherein said curing process is selected from the group consistingof heat, humidity, pressure, radiation, and the vapors of across-linking agentSince proteins in general contain lysine and arginineresidues with amino reactive groups and serine, threonine and tyrosinewith hydroxyl side chains, one preferable and well accepted method ofcrosslinking proteins is with aldehydes or dialdehydes. Formaldehyde,carbodiimide and more preferably glutaraldehyde are well known in theart as methods of crosslinking proteins. The crosslinked protein isrendered insoluble but its ability to be degraded by proteases in thebody is maintained. The amount of crosslinking can be controlled by theratio of the crosslinking agent to the protein side groups with which itis to react. The more heavily crosslinked the protein the less solubleit will be and the more slowly it will be biodegraded by proteaseenzymes. For example the most preferable amount of glutaraldehyde forcrosslinking hydrolyzed gelatin has been found to be the amount that isstoicheometric with the amino side chains in the protein.

While for certain uses (e.g. the insertion of a depot of drug into thebody where a crevice is not available) the insertion of liquidformulations may be easier than a preformed solid dosage form, ingeneral a preformed solid dosage form is easier to handle and insertinto an open crevice and gives better control of the drug dose. Theincorporation of the drug in the delivery device must be uniform so asto keep tight control over the dosing level. If one chooses crosslinkedproteins as the delivery device of choice because of its delivery,degradation, and non toxic by-product properties, one is faced with aproblem of incorporating non water soluble drugs into such a device.While many methods exist to form homogeneous mixtures, the drug wouldnot be incorporated into the matrix in a complete fashion. When all thecomponents are dissolved in a solution the mixture of the componentsupon solidification is considerably more intimate and the control of thedrug delivery from the crosslinked protein is much enhanced.

Many drugs that are not soluble to any extent in aqueous solutions aresoluble in alcohol solutions. The alcohols useful with the aqueoussolutions of the proteins are preferably ethanol, isopropanol andn-propanol, with ethanol being the most preferable. Proteins of lowmolecular weight and a relatively high proportion of hydrophobic sidegroups do not precipitate from aqueous solution when a certainproportion of alcohol is added. A preferable protein with regards tothis property is hydrolyzed gelatin of number average molecular weightless than 20,000 and most preferably less than 13,000 but more than1000. This protein is stable in solutions that contain over 50% ethanolallowing the incorporation of aqueous solutions of non water solubledrugs that are soluble in the alcohol.

A solid device for insertion into a body crevice needs to be rigidenough to be inserted against a certain amount of back pressureexhibited by the frictional forces on the device when being inserted,but pliable enough so as not to break and pliable enough to conform tothe contour of the crevice. In one embodiment, plasticizers are added toformulations to give the desired flexibility. For crosslinked proteinand/or non water soluble polymer formulations, possible plasticizers areglycol derivatives, phthalates, citrate derivatives, benzoates, butyl orglycol esters of fatty acids, refined mineral oils, camphor, oleic acid,castor oil, corn oil and sugar alcohols. The type and the amount of theplasticizer will control the flexibility of the composition. Preferredplasticizers for the device which comprising crosslinked protein aresorbitol and glycerin with glycerin being the most preferredplasticizer. For a device comprising a non water soluble polymer, apreferred plasticizer is triethyl citrate. The preferred amount ofplasticizer is between 1, 2, 3, 4, 5, 6 or 7% and 15, 16, 17, 18, 19,20, 21, 22, 23, 24 or 25% (w/w of the drug delivery composition), andmost preferably 6-16%.

A variety of pharmacological agents may be incorporated into theprecursor solutions and thus into the drug delivery devices describedherein. In one embodiment, more than one pharmacological agent can beincorporated into a drug delivery device whether they be of the sametherapeutic category (e.g. two or more anti-inflammatory drugs) or ofdifferent therapeutic categories, with the exception of ananti-bacterial agent (e.g. one or more anti-fungal drugs, or one or moreanti-inflammatory drug and one or more anti-neoplastic drug). In oneembodiment, the anti-inflammatory agent is hydrophobic or non-watersoluble. The amount of drug to be incorporated into the drug deliverycomposition depends on the intended therapeutic use and can bedetermined by one skilled in the art. The drug can be present in thedrug delivery composition from 0.1 to 50% (w/w), most preferably 15-45%(w/w).

Examples of antibacterial agents include sulfonamides, phenolics,quaternary ammonium salts, chlorhexidine (CHX) and salts thereof,antibiotics such as penicillins, cephalosporins, tetracycline,doxycycline, chloramphenicol, and erythromycin. A preferredantibacterial agent is CHX di-gluconate.

A particularly preferred anti-inflammatory pharmacological agent forthis delivery device is one capable of healing the periodontal tissue orone that can retard bone resorption or induce bone regrowth. Examples ofsuch drugs are bone growth factors, bisphosphonates and FBP. Deliverydevices with these drugs may be inserted surgically in the body inproximity to the site where their effect is required. The drug will bereleased over a prolonged period of time while the delivery device isbiodegraded into harmless products. Alternately, the delivery device canbe inserted into body cavities in proximity to the site of action, suchas a periodontal pocket. One embodiment of this invention is to theincorporation of FBP into the delivery device and its insertion eitherinto a periodontal pocket for the arresting of alveolar bone resorptionand for the initiation of bone regrowth, or its implantation under thegum during periodontal surgery. A further preferred usage of the drugdelivery device is as an adjunct treatment to periodontal surgery whereit is inserted into the periodontal pockets both before and after theperiodontal surgery.

Further embodiments of this invention are to the incorporation of drugsthat will treat inflammation in a site in the body where theinflammation needs to be treated. Again, the drug delivery device can beinserted into body crevices that exist or are implanted in a surgicalprocedure. Examples of drugs whose efficacious amounts for use in thedelivery device of the invention may be determined includeanti-inflammatory agents including steroidal anti-inflammatory agentssuch as dexamethasone, budesonide, beclomethasone, and hydrocortisone.

Anti-Inflammatory agents are a well known class of pharmaceutical agentswhich reduce inflammation by acting on body mechanisms (Stedman'sMedical Dictionary 26 ed., Williams and Wilkins, (1995); Physicians DeskReference 51 ed., Medical Economics, (1997)).

Anti-inflammatory agents useful in the methods of the invention includeNon-steroidal Anti-Inflammatory Agents (NSAIDS). NSAIDS typicallyinhibit the body's ability to synthesize prostaglandins. Prostaglandinsare a family of hormone-like chemicals, some of which are made inresponse to cell injury. Specific NSAIDS approved for administration tohumans include naproxen sodium, diclofenac, sulindac, oxaprozin,diflunisal, aspirin, piroxicam, indomethocin, etodolac, ibuprofen,fenoprofen, ketoprofen, mefenamic acid, nabumetone, tolmetin sodium, andketorolac tromethamine.

Other anti-inflammatory agents useful in the methods of the inventioninclude salicylates, such as, for example, salicilic acid, acetylsalicylic acid, choline salicylate, magnesium salicylate, sodiumsalicylate, olsalazine, and salsa late.

Other anti-inflammatory agents useful in the methods of the inventioninclude cyclooxygenase (COX) inhibitors. COX catalyzes the conversion ofarachidonate to prostaglandin H2 (PGH2); a COX inhibitor inhibits thisreaction. COX is also known as prostaglandin H synthase, or PGHsynthase. Two Cox genes, Cox-1 and Cox-2 have been isolated in severalspecies. COX-2 is tightly regulated in most tissues and usually onlyinduced in abnormal conditions, such as inflammation, rheumatic andosteo-arthritis, kidney disease and osteoporosis. COX-1 is believed tobe constitutively expressed so as to maintain platelet and kidneyfunction and integral homeostasis. Typical COX inhibitors useful in themethods of the invention include etodolac, celebrex, meloxicam,piroxicam, nimesulide, nabumetone, and rofecoxib.

In one embodiment of the invention, anti-inflammatory agents that can beincorporated into a polymer matrix for administration in the methods ofthe invention include: 3-Amino-4-hydroxybutyric Acid, Aceclofenac,Acemetacin, Acetaminosalol, Alclofenac, Alminoprofen, α-Bisabolol,Paranyline, Amfenac, Bromfenac, Benoxaprofen, Benzpiperylon,Bermoprofen, Bromosaligenin, Bucloxic Acid, Bufexamac, Bumadizon,Butibufen, Carprofen, Cinmetacin, Clidanac, Clopirac, Diclofenac,Diclofenac Sodium, Diflunisal, Ditazol, Enfenamic Acid,ε-Acetamidocaproic Acid Bendazac, Etodolac, Etofenamate, Felbinac,Fenbufen, Fenclozic Acid, Fendosal, Fenoprofen, Fentiazac, Fepradinol,Flufenamic Acid, Flunoxaprofen, Flurbiprofen, Gentisic Acid,Glucametacin, Glycol Salicylate, Ibufenac, Ibuprofen, Ibuproxam,Indomethacin, Indoprofen, Isofezolac, Isoxepac, Isoxicam, Ketoprofen,Ketorolac, Lomoxicam, Lonazola, Lonazolac, Loxoprofen, MeclofenamicAcid, Mefenamic Acid, Meloxicam, Mesalamine, Metiazinic Acid,Mofebutazone, Mofezolac, Naproxen, Niflumic Acid, Olsalazine, Oxaceprol,Oxametacine, Oxaprozin, Oxicams, Oxyphenbutazone, Paranyline,Parsalmide, Perisoxal, Phenyl Salicylate, Pirazolac, Piroxicam,Pirprofen, Pranoprofen, Proprionic Acids, Protizinic Acid, Salacetamide,Salicilic Acid, Salicylamide O-Acetic Acid, Salicylsulfuric Acid,Salsalate, Sulfasalazine, Sulindac, Suprofen, Suxibuzone, Talniflumate,Tenoxicam, Terofenamate, Tiaprofenic Acid, Tiaramide, Tinoridine,Tolfenamic Acid, Tolmetin, Tropesin, Xenbucin, Ximoprofen, Zaltoprofen,Zileuton and Zomepirac.

For any anti-inflammatory agent referred to herein by a trade name it isto be understood that either the trade name product or the activeingredient possessing anti-inflammatory activity from the product can beused.

In one embodiment, the anti-inflammatory agent and the water-insolublepolymer are present at a relative weight ratio which ranges from about2:1 to about 1:3.

In another embodiment, the plasticizing agent and the polymer arepresent at a relative weight ratio which ranges from about 1:10 to about1:2.

A further embodiment of this invention is the incorporation of the NSAIDdrugs listed above or morphine, codeine, or other anti pain agents forthe control of pain from a localized site in the body. Insertion of thedrug delivery device will allow efficacious levels of the drug to bedelivered over a prolonged period at the site of action.

Further embodiments of this invention are to the incorporation ofanti-neoplastic agents including methotrexate, 5-fluorouracil,tamoxifen, chlorambucil, melphalan, mercaptopurine, etoposide, anddoxorubicin. Surgical implantation of the device in proximity of thetumor will give high concentration of the chemotherapeutic agent at thetumor site.

When incorporating drugs into the precursor solution it may beadvantageous to include surface active agents in order to enhancesolubilization of the components and to stabilize the solutions. Thesurface active agent may be present in amounts that vary from 0 to about20% of the delivery device. Surfactants that may be of use informulating the precursor solutions of this invention includepolysorbate 80 (Tween 80), anionic emulsifying wax (Crodex A), andsodium lauryl sulfate. In one embodiment of this invention the surfaceactive agents are omitted.

This precursor solution can be formed into various drug delivery devicesthat are polymeric solids that may be cast as films, pellets, granules,cylinders or any other convenient shape for the task at hand. The mostpreferable form is when cast as thin films. To form thin films theprecursor mixture poured into leveled trays and is dried at roomtemperature. In one embodiment, the film is from about 3 to about 6 mmin length and from about 1 to about 5 mm in width and from about 0.01 toabout 1.0 mm in thickness.

One preferred embodiment of the invention comprises a water solubleprotein that is stable in solutions of more than 50% water/alcohol, i.e.hydrolyzed gelatin of number average molecular weight less than 20000most preferably less than 13,000 but more than 1000. The alcohol used isethanol and the ethanol to water ratio is between 0.1- to 1.0.

The first preferred composition of the precursor solution is hydrolyzedgelatin 6.8 parts, FBP 2.0 parts, glycerin 1.2 parts, glutaraldehydesolution (25% in water) 2.2 parts, Polysorbat 80 0.2 parts, water 72.0parts and ethanol 15.6 parts. This formulation when dried to a thin filmof 0.35 mm thickness gives a drug delivery device with the followingcomposition:

crosslinked hydrolyzed gelatin 68.4% FBP 18.9% glycerin 10.9% polysorbat80 1.8%

The second preferred composition of the precursor solution is hydrolyzedgelatin 8.1 parts, FBP 3.8 parts, glycerin 1.4 parts, glutaraldehydesolution (25% in water) 1.5 parts, Polysorbat 80 0.3 parts, water 69.0parts and ethanol 15.9 parts. This formulation when dried to a thin filmof 0.35 mm thickness gives a drug delivery device with the followingcomposition:

crosslinked hydrolyzed gelatin 54.2% FBP 31.0% glycerin 12.9% polysorbat80 1.9%

The third preferred composition of the precursor solution is hydrolyzedgelatin 11.0 parts, FBP 4.9 parts, glycerin 2.0 parts, glutaraldehydesolution (25% in water) 3.7 parts, Polysorbat 80 0.2 parts, water 59.3parts and ethanol 19.0 parts. This formulation when dried to a thin filmof 0.35 mm thickness gives a drug delivery device with the followingcomposition:

crosslinked hydrolyzed gelatin 62.7% FBP 25.7% glycerin 10.3% polysorbat80 1.3%

The thin films of the drug delivery device can be cut into anyconvenient shape. For use in a periodontal pocket the films can be cutto the dimensions of about 4×5×0.35 mm which is a size appropriate forinserting into a periodontal pocket. The thin film embodiments of thisinvention can be cut into any convenient shape for implantation orinsertion in the body.

Treatment of patients with periodontitis according to the method of theinvention is another aspect of the current invention.

Delivery devices containing steroidal or NSAID drugs can be inserted ator in proximity to a site suffering from an inflammatory process.Delivery devices containing FBP or other NSAIDs or other bone growthfactors can be inserted at or in proximity to a site that requires bonegrowth. Delivery devices containing antibiotics, antimicrobials, or antifungal agents can be inserted at or in proximity to a site where theaction of these drugs are called for and delivery devices containinganti-neoplastic agents can be inserted at or in proximity to a tumorsite.

The full contents of all publications mentioned in this specificationare hereby incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carriedout in practice, embodiments will now be described, by way ofnon-limiting example only, with reference to the accompanying drawings,in which:

FIGS. 1 & 2 are graphs showing the relationship between PPD in mm as afunction of time after insertion of a solid oral delivery device (chip).FIG. 1 shows results using the FBP chip and FIG. 2 shows results usingthe CHX chip.

DETAILED DESCRIPTION OF EMBODIMENTS

The aim of the present randomized, double-blinded, parallel, 2-armclinical study was to examine the safety and efficacy of multipleapplication of a CHX Chip and FBP Chip in subjects with chronicperiodontitis. The Chips (=solid oral delivery device) were prepared asdisclosed in U.S. Pat. No. 5,023,769 and in WO 2004/084873.

Sixty subjects were accepted and randomized into CHX and FBP groups.Following oral hygiene instruction and full mouth scaling, baselinemeasurements of PPD and Bleeding On Probing (BOP) were performed.

Example 1

The efficacy of the FBP chip was investigated under 2 different clinicalprotocols and PPD reduction was measured in mm. In the first clinicalstudy the FBP Chip was inserted into the periodontal pocket every 6weeks. In the second clinical study the FBP Chip was inserted into theperiodontal pocket every week for the first month and every other weekfor the second month.

The results are presented in FIG. 1. It may be seen that while the every6 Wks. protocol resulted in a PPD reduction of 1.86 mm after 6 months,the every 1-2 Wks. protocol resulted in a PPD reduction of 2.33 mm afteronly 2 months. Thus, it may be seen that the increased frequency ofinsertion gave superior results.

Example 2

The efficacy of the CHX chip was investigated under 3 different clinicalprotocols and PPD reduction was measured in mm. In the first clinicalstudy CHX was inserted into the periodontal pocket every 3 months. Inthe second clinical study CHX Chip was inserted into the periodontalpocket every 6 Wks. In the third clinical study CHX Chip was insertedinto the periodontal pocket every week for the first month and everyother week for the second month.

The results are presented in FIG. 2. It may be seen that while the CHXChip every 3 months protocol resulted in a PPD reduction of 0.95 mmafter 9 months, the protocol of every 6 Wks resulted in a PPD reductionof 1.62 mm after 6 months and the protocol of CHX Chip every 1-2 Wksresulted in a further PPD reduction of 2.08 mm after only 2 months.

CONCLUSION

increased frequency of chip insertion containing either CHX or FBP intoperiodontal pockets resulted in a significant improvement in theperiodontal condition in the periodontal pockets sites in a shorterperiod of time.

1. A method for treating inflammation in a site in periodontal tissue of a patient in need thereof, the method comprising inserting an oral delivery device into said site at a frequency of about every 7 days to about once every 2 weeks, wherein the oral delivery device is a controlled release solid unit dosage form comprising a biodegradable pharmaceutically acceptable matrix and a therapeutically effective amount of an active ingredient selected from the group consisting of i) at least one anti-inflammatory agent, ii) at least one antibacterial agent, and iii) a combination of at least one anti-inflammatory agent and at least one antibacterial agent.
 2. The method of claim 1, wherein the oral delivery device is inserted into said site at a frequency of about once every 2 weeks.
 3. The method of claim 2, wherein the oral delivery device is inserted into said site for a period of the earlier of three months or until healing of the periodontal tissue.
 4. The method of claim 1, wherein the oral delivery device is inserted into said site at a frequency of once every 7, 8, 9, 10, 11, 12, 13 or 14 days.
 5. The method of claim 1, wherein the oral delivery device is inserted into said site at least 4, 5 or 6 consecutive times.
 6. The method of claim 5, wherein the controlled release solid unit dosage form is in the form of a film, pellet, granule or cylinder.
 7. The method of claim 6, wherein the controlled release solid unit dosage form is in the form of a film.
 8. The method of claim 7, wherein the film has a length of from about 3 to about 6 mm, a width of from about 1 to about 5 mm, and a thickness of from about 0.01 to about 1.0 mm.
 9. The method of claim 1, wherein the biodegradable pharmaceutically acceptable matrix comprises cross-linked water-soluble protein.
 10. The method of claim 9, wherein the cross-linked water-soluble protein comprises hydrolyzed gelatin cross-linked with glutaraldehyde.
 11. The method of claim 1, comprising first inserting into said site an oral delivery device comprising a therapeutically effective amount of at least one anti-inflammatory agent followed by inserting into said site an oral delivery device comprising a therapeutically effective amount of at least one antibacterial agent.
 12. The method of claim 1, comprising first inserting into said site an oral delivery device comprising a therapeutically effective amount of at least one anti-inflammatory agent followed by inserting into said site an oral delivery device comprising a therapeutically effective amount of a combination of at least one anti-inflammatory agent and at least one antibacterial agent.
 13. The method of claim 1, wherein the oral delivery device comprises between about 0.1 to 50% (w/w) of an active pharmaceutical ingredient.
 14. The method of claim 13, wherein the oral delivery device comprises between about 15 to 45% (w/w) of an active pharmaceutical ingredient.
 15. The method of claim 1, wherein the active ingredient is a non-steroidal anti-inflammatory drug (NSAID).
 16. The method of claim 15, wherein the non-steroidal anti-inflammatory drug (NSAID) is flurbiprofen (FBP).
 17. The method of claim 1, wherein the active ingredient is an antibacterial agent comprising a sulfonamide, a phenolic, a quaternary ammonium salt, chlorhexidine or a salt thereof, or an antibiotic.
 18. The method of claim 17, wherein the antibiotic comprises penicillin, cephalosporin, tetracycline, doxycycline, chloramphenicol, or erythromycin.
 19. The method of claim 17, wherein the antibacterial agent is chlorhexidine or a salt thereof.
 20. The method of claim 19, wherein the antibacterial agent is chlorhexidine digluconate.
 21. The method of claim 1, wherein the oral delivery device further comprises a plasticizing agent.
 22. The method of claim 21, wherein the plasticizing agent is glycerin.
 23. The method of claim 1, wherein the oral delivery device further comprises at least one of a surfactant, a wetting agent, a suspending agent and a dispersing agent.
 24. The method of claim 1, wherein the treatment is an adjunct treatment to periodontal surgery, where the oral delivery device is inserted into said site before and/or after the periodontal surgery.
 25. The method of claim 1, wherein the treatment comprises implantation of the oral delivery device in a surgical procedure.
 26. The method of claim 1, wherein the treatment is an adjunct treatment to scaling. 